Crucial knowledge gaps hinder our ability to treat nicotine dependence optimally. We know too little about the relative efficacies of pharmacotherapies in both clinical trials and real-world contexts. We know too little about how to deliver treatment: e.g., how to match patients with pharmacotherapies, how to incorporate treatment seamlessly into health care delivery systems and how to combine pharmacotherapies. In addition, we know too little about the global, long-term consequences of quit attempts: e.g., the downstream physiological, psychosocial, and health care utilization effects of continuing to smoke versus successfully quitting. Finally, we lack understanding of the mechanisms by which treatments work. These gaps will be addressed via four research projects and supportive cores. The first project (N=1520) will contrast efficacies of five different pharmacotherapies and a placebo, explore their mechanisms of action and yield algorithms for their optimal use. The second project will follow from the first project participants for at least 3 years and capture the diverse physical and psychosocial health outcomes of a quit attempt. The third project (N=1320) will study the active pharmacotherapies used in the first project, but in an effectiveness, primary care context. Data will address treatment utilization, success, and validate treatment algorithms. The fourth project will track from the third project subjects along with anonymous controls and reveal the impact of cessation on health care utilization and costs within a large network of primary care clinics. In addition, the UW-TTURC proposal includes an Administrative Core providing shared resources and infrastructure, a Career Development Core to increase the number of clinician-scientists entering the field of tobacco control research, and a Developmental Research Core to support innovative tobacco control research. The proposed work will advance the understanding and effectiveness of tobacco dependence treatment through integrated transdisciplinary research and result in more smokers quitting successfully.